MicroRNAs Regulate p21Waf1/Cip1 Protein Expression and the DNA Damage Response in Human Embryonic Stem Cells

Doležalová, Dáša; Mráz, Marek; Bárta, Tomáš; Plevová, Karla; Vinarský, Vladimír; Holubcová, Zuzana; Jaroš, Josef; Dvořák, Petr; Pospı́šilová, Šárka; Hampl, Aleš

doi:10.1002/stem.1108

Cited by 106 publications

(85 citation statements)

References 48 publications

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“…Luciferase reporter assay was performed using the LightSwitch Luciferase Assay System (SwitchGear Genomics), according to the manufacturer's protocol, as described previously 40 (see supplemental Methods).…”

Section: Luciferase Assaymentioning

confidence: 99%

miR-150 influences B-cell receptor signaling in chronic lymphocytic leukemia by regulating expression of GAB1 and FOXP1

Mráz

Chen

Rassenti

et al. 2014

Blood

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140

132

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Key Points• The most abundant miRNA in CLL, miR-150, is expressed at lower levels in cases with unfavorable clinicobiological markers and worse prognosis.• miR-150 regulates expression of genes encoding proteins that modulate BCR signaling in CLL.We examined the microRNAs (miRNAs) expressed in chronic lymphocytic leukemia (CLL) and identified miR-150 as the most abundant, but with leukemia cell expression levels that varied among patients. CLL cells that expressed z-chain-associated protein of 70 kDa (ZAP-70) or that used unmutated immunoglobulin heavy chain variable (IGHV) genes, each had a median expression level of miR-150 that was significantly lower than that of ZAP-70-negative CLL cells or those that used mutated IGHV genes. In samples stratified for expression of miR-150, CLL cells with low-level miR-150 expressed relatively higher levels of forkhead box P1 (FOXP1) and GRB2-associated binding protein 1 (GAB1), genes with 39 untranslated regions having evolutionary-conserved binding sites for miR-150. High-level expression of miR-150 could repress expression of these genes, which encode proteins that enhance B-cell receptor signaling, a putative CLL-growth/ survival signal. Also, high-level expression of miR-150 was a significant independent predictor of longer treatment-free survival or overall survival, whereas an inverse association was observed for high-level expression of GAB1 or FOXP1 for overall survival. This study demonstrates that expression of miR-150 can influence the relative expression of GAB1 and FOXP1 and the signaling potential of the B-cell receptor, thereby possibly accounting for the noted association of expression of miR-150 and disease outcome. (Blood. 2014;124(1):84-95)

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Section: Luciferase Assaymentioning

confidence: 99%

miR-150 influences B-cell receptor signaling in chronic lymphocytic leukemia by regulating expression of GAB1 and FOXP1

Mráz

Chen

Rassenti

et al. 2014

Blood

Self Cite

140

132

View full text Add to dashboard Cite

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“…Variable outcomes are likely to be correlated with the relative activation of P21. P21 regulates functions of many progenitors and stem cells, including cancer stem cells, neural stem cells (NSCs), hematopoietic stem cells (HSCs), hair follicle stem cells, mesenchymal stem cells and ESC/iPSCs (van den Bos et al, 1998;Kippin et al, 2005;Orford and Scadden, 2008;Moriguchi et al, 2010;Dolezalova et al, 2012;Lee et al, 2013). P21 governs self-renewal of colon cancer-initiating cells through cell-cycle restriction and protection from DNA damage accumulation (O'Brien et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

SOX9 accelerates ESC differentiation to three germ layer lineages by repressing SOX2 expression through P21 (WAF1/CIP1)

Yamamizu

Schlessinger

2014

Development

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Upon removal of culture conditions that maintain an undifferentiated state, mouse embryonic stem cells (ESCs) differentiate into various cell types. Differentiation can be facilitated by forced expression of certain transcription factors (TFs), each of which can generally specify a particular developmental lineage. We previously established 137 mouse ESC lines, each of which carried a doxycycline-controllable TF. Among them, Sox9 has unique capacity: its forced expression accelerates differentiation of mouse ESCs into cells of all three germ layers. With the additional use of specific culture conditions, overexpression of Sox9 facilitated the generation of endothelial cells, hepatocytes and neurons from ESCs. Furthermore, Sox9 action increases formation of p21 (WAF1/CIP1), which then binds to the SRR2 enhancer of pluripotency marker Sox2 and inhibits its expression. Knockdown of p21 abolishes inhibition of Sox2 and Sox9-accelerated differentiation, and reduction of Sox2 2 days after the beginning of ESC differentiation can comparably accelerate mouse ESC formation of cells of three germ layers. These data implicate the involvement of the p21-Sox2 pathway in the mechanism of accelerated ESC differentiation by Sox9 overexpression. The molecular cascade could be among the first steps to program ESC differentiation.

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“…For example, MICA and MICB have been reported to be regulated by endogenous miRNAs in tumours and as a result of infection with cytomegalovirus (Stern-Ginossar et al 2008). Since miRNAs appear to play a role in regulating cellular senescence (Feliciano et al 2011;Liu et al 2012;Benhamed et al 2012) and their expression is altered in response to DNA damage (Dolezalova et al 2012;Wang and Taniguchi 2013), it is possible that changes in miRNA expression also regulate the expression of immune ligands in senescent cells.…”

Section: The Relationship Between Cell Senescence and Immune Ligand Ementioning

confidence: 99%

Cellular senescence: from growth arrest to immunogenic conversion

Burton

Faragher

2015

AGE

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Cellular senescence was first reported in human fibroblasts as a state of stable in vitro growth arrest following extended culture. Since that initial observation, a variety of other phenotypic characteristics have been shown to co-associate with irreversible cell cycle exit in senescent fibroblasts. These include (1) a proinflammatory secretory response, (2) the up-regulation of immune ligands, (3) altered responses to apoptotic stimuli and (4) promiscuous gene expression (stochastic activation of genes possibly as a result of chromatin remodeling). Many features associated with senescent fibroblasts appear to promote conversion to an immunogenic phenotype that facilitates self-elimination by the immune system. Pro-inflammatory cytokines can attract and activate immune cells, the presentation of membrane bound immune ligands allows for specific recognition and promiscuous gene expression may function to generate an array of tissue restricted proteins that could subsequently be processed into peptides for presentation via MHC molecules. However, the phenotypes of senescent cells from different tissues and species are often assumed to be broadly similar to those seen in senescent human fibroblasts, but the data show a more complex picture in which the growth arrest mechanism, tissue of origin and species can all radically modulate this basic pattern. Furthermore, wellestablished triggers of cell senescence are often associated with a DNA damage response (DDR), but this may not be a universal feature of senescent cells. As such, we discuss the role of DNA damage in regulating an immunogenic response in senescent cells, in addition to discussing less established Batypical^senescent states that may occur independent of DNA damage.

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MicroRNAs Regulate p21Waf1/Cip1 Protein Expression and the DNA Damage Response in Human Embryonic Stem Cells

Cited by 106 publications

References 48 publications

miR-150 influences B-cell receptor signaling in chronic lymphocytic leukemia by regulating expression of GAB1 and FOXP1

miR-150 influences B-cell receptor signaling in chronic lymphocytic leukemia by regulating expression of GAB1 and FOXP1

SOX9 accelerates ESC differentiation to three germ layer lineages by repressing SOX2 expression through P21 (WAF1/CIP1)

Cellular senescence: from growth arrest to immunogenic conversion

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